Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects

Abstract

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.

Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

“…In addition, a homozygous deletion‐inversion‐deletion overlapping CEP78 has recently been described in a CRDHL case (Sanchis‐Juan et al, 2018). Several functional studies at the protein level point to a loss‐of‐function (LOF) effect with decreased amounts of protein, correct subcellular localization, and importantly, elongated primary cilia in patients' fibroblasts, a feature that has been observed in other ciliopathies as well (Mokrzan, Lewis, & Mykytyn, 2007; Nikopoulos et al, 2016).…”

“…Biallelic inactivating variants in CEP78 , encoding the Centrosomal Protein 78 (MIM# 617110), have been linked to autosomal recessive cone‐rod dystrophy with hearing loss (CRDHL; MIM# 617236; Namburi et al, 2016; Nikopoulos et al, 2016). The unique combination of CRD and sensorineural hearing impairment was stated to be distinct from the well‐known Usher syndrome, characterized by recessively inherited retinitis pigmentosa (RP) and congenital mild to severe hearing impairment or complete sensorineural deafness.…”

“…The unique combination of CRD and sensorineural hearing impairment was stated to be distinct from the well‐known Usher syndrome, characterized by recessively inherited retinitis pigmentosa (RP) and congenital mild to severe hearing impairment or complete sensorineural deafness. Up to now, seven different truncating mutations have been reported in CEP78 , segregating in CRDHL families of different origins (Fu et al, 2016; Namburi et al, 2016; Nikopoulos et al, 2016). Furthermore, a homozygous CEP78 ‐truncating variant was found in a family with reported nonsyndromic RP (MIM# 268000; de Castro‐Miró et al, 2016).…”

“…Furthermore, a homozygous CEP78 ‐truncating variant was found in a family with reported nonsyndromic RP (MIM# 268000; de Castro‐Miró et al, 2016). So far, only frameshift and splice site variants have been identified, with the latter all displaying exon skipping at the RNA level (Fu et al, 2016; Namburi et al, 2016; Nikopoulos et al, 2016). In addition, a homozygous deletion‐inversion‐deletion overlapping CEP78 has recently been described in a CRDHL case (Sanchis‐Juan et al, 2018).…”

Identification of novel USH2A mutations in patients with autosomal recessive retinitis pigmentosa via targeted next‑generation sequencing

“…Therefore, identifying additional disease genes involved in rP is important for genetics diagnosis. next-generation sequencing (nGS) has become one of the most important tools for the identification of disease-causing genes (11)(12)(13)(14)(15)(16)(17)(18). in previous studies, a targeted nGS method has been used successfully to systematically screen coding regions of known retinal genes to identify pathological mutations (19)(20)(21).…”